Extracellular matrix consists primarily of collagens, proteoglycans, elastin, and fibronectin. The inappropriate synthesis of extracellular matrix proteins and/or the synthesis of aberrant forms of such proteins is associated with wide range of deleterious conditions, including many rare heritable diseases as well as more commonly acquired disorders, such as fibrotic skin disease, pulmonary fibrosis, osteoarthritis, vascular restenosis, and the like, e.g., Weiss and Jayson, Editors, Collagen in Health and Disease (Churchill Livingstone, Edinburgh, 1982); Gardner, Editor, Pathological Basis of the Connective Tissue Diseases (Lea & Febiger, Philadelphia, 1992).
Many of these conditions are associated with very complex biological responses to physical, chemical, and/or biological insults. Such responses include the proliferation and migration of a variety of cell types and the synthesis of a growth factors that contribute to or modify the response. For example, vascular disorders, such as atherosclerosis and vascular restenosis, are associated with local cell proliferation and migration, as well as the production of several classes of structural proteins and many growth factors, including platelet-derived growth factor, basis fibroblastic growth factor, tumor necrosis factor .alpha., interleukin-1, prostaglandins, and a variety of proto-oncogenes, e.g., Ross, Nature, 362: 801-809 (1993); and Morishita et al, Proc. Natl. Acad. Sci., 90:8474-8478 (1993). Unfortunately, the precise role of these factors in the various disease processes is not well understood.
The tremendous economic impact of disorders associated with inappropriate production of extracellular matrix proteins, especially vascular disorders, has served as a strong impetus to develop drugs or other methods of treatment to cure or ameliorate their debilitating effects. In this class of disease, as well as others, where a disease condition is associated with the apparent aberrant expression of a endogenous gene, the use of so called antisense compounds provides many advantages, e.g. Milligan et al, J. Med. Chem., 36:1923-1937 (1993); Uhlmann and Peyman, Chemical Reviews, 90:543-584 (1990); Goodchild, Bioconjugate Chemistry, 1:165-187 (1990); Crooke, Ann. Rev. Pharmacol. Toxicol., 32:329-376 (1992); Stein et al, Science, 261:1004-1012 (1993); and the like.
A particularly compelling advantage of the antisense approach is that one need not carry out one or more initial screening steps to identify candidate compounds capable of binding to a therapeutic target. If the aberrant expression of a gene is known to cause a disease for which a drug is sought, then the structures of candidate antisense drugs are determined automatically from the nucleotide sequence of the aberrantly expressed gene. One need only provide an oligonucleotide or an analog thereof capable of forming a stable duplex or triplex with such a gene, or associated target polynucleotide, based on Watson Crick or Hoogsteen binding, respectively. The specifically bound antisense compound then either renders the respective targets more susceptible to enzymatic degradation, blocks translation or processing, or otherwise blocks or inhibits the function of a target polynucleotide.
It would be highly advantageous if particular genes were identified whose expression were causally related to the synthesis of structural proteins, such as collagen, that contribute to disease conditions. Such identification would immediately lead to the prospect of treatments for a number of disorders associated with the excess synthesis of such proteins by the antisense approach.